ATM protein and p53-serine 15 phosphorylation in ataxia-telangiectasia (AT) patients and at heterozygotes

• Published in: British journal of cancer 2000-06, Vol.82 (12), p.1938-1945
• Main Authors: Delia, D, Mizutani, S, Panigone, S, Tagliabue, E, Fontanella, E, Asada, M, Yamada, T, Taya, Y, Prudente, S, Saviozzi, S, Frati, L, Pierotti, M A, Chessa, L
• Format: Article
• Language: English
• Subjects: Asymptomatic; Ataxia; Ataxia Telangiectasia - metabolism; Ataxia Telangiectasia Mutated Proteins; ATM gene; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Cycle; Cell Cycle Proteins; Cells, Cultured; Complex syndromes; DNA-Binding Proteins; Drug Resistance; Epidemiology; Heterozygote; Humans; Kinases; Lymphoma; Medical genetics; Medical research; Medical sciences; Molecular Medicine; Mutation; Oncology; Phosphorylation; Protein expression; Protein Serine-Threonine Kinases - metabolism; Proteins; Radiation; Regular; regular-article; Serine - metabolism; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1054/bjoc.2000.1168

ATM (ataxia-telangiectasia mutated) gene plays a central role in the DNA-damage response pathway. We characterized the ATM protein expression in immortalized cells from AT and AT-variant patients, and heterozygotes and correlated it with two ATM-dependent radiation responses, G1 checkpoint arrest and p53-Ser 15 phosphorylation. On Western blots, the full-length ATM protein was detected in eight of 18 AT cases, albeit at 1–32% of the normal levels, whereas a truncated ATM protein was detected in a single case, despite the prevalence among cases of truncation mutations. Of two ataxia without telangiectasia [A-(T)] cases, one expressed 20% and the other ~70% of the normal ATM levels. Noteworthy, among ten asymptomatic heterozygous carriers for AT, normal amounts of ATM protein were found in one and reduced by 40–50% in the remaining cases. The radiation-induced phosphorylation of p53 protein at serine 15, largely mediated by ATM kinase, was defective in AT, A(-T) and in 2/4 heterozygous carriers, while the G1 cell cycle checkpoint was disrupted in all AT and A(-T) cases, and in 3/10 AT heterozygotes. Altogether, our study shows that AT and A(-T) cases bearing truncation mutations of the ATM gene can produce modest amounts of full-length (and only rarely truncated) ATM protein. However, this limited expression of ATM protein provides no benefit regarding the ATM-dependent responses related to G1 arrest and p53-ser15 phosphorylation. Our study additionally shows that the majority of AT heterozygotes express almost halved levels of ATM protein, sufficient in most cases to normally regulate the ATM-dependent DNA damage-response pathway.